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Nucleic Acids Research Advance Access originally published online on March 4, 2008
Nucleic Acids Research 2008 36(8):2530-2546; doi:10.1093/nar/gkn096
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Nucleic Acids Research, 2008, Vol. 36, No. 8 2530-2546
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Bioinformatic and functional analysis of RNA secondary structure elements among different genera of human and animal caliciviruses

Peter Simmonds1,*, Ioannis Karakasiliotis2, Dalan Bailey2, Yasmin Chaudhry2, David J. Evans3 and Ian G. Goodfellow2

1Centre for Infectious Diseases, University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, 2Calicivirus Research Group, Department of Virology, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG and 3Department of Biological Sciences, University of Warwick, Coventry, CV4 7AL, UK

*To whom correspondence should be addressed. Tel: +44 131 650 7927; Fax: +44 131 650 6511; Email: peter.simmonds{at}ed.ac.uk

Received November 1, 2007. Revised February 2, 2008. Accepted February 18, 2008.

The mechanism and role of RNA structure elements in the replication and translation of Caliciviridae remains poorly understood. Several algorithmically independent methods were used to predict secondary structures within the Norovirus, Sapovirus, Vesivirus and Lagovirus genera. All showed profound suppression of synonymous site variability (SSSV) at genomic 5' ends and the start of the sub-genomic (sg) transcript, consistent with evolutionary constraints from underlying RNA structure. A newly developed thermodynamic scanning method predicted RNA folding mapping precisely to regions of SSSV and at the genomic 3' end. These regions contained several evolutionarily conserved RNA secondary structures, of variable size and positions. However, all caliciviruses contained 3' terminal hairpins, and stem–loops in the anti-genomic strand invariably six bases upstream of the sg transcript, indicating putative roles as sg promoters. Using the murine norovirus (MNV) reverse-genetics system, disruption of 5' end stem–loops produced ~15- to 20-fold infectivity reductions, while disruption of the RNA structure in the sg promoter region and at the 3' end entirely destroyed replication ability. Restoration of infectivity by repair mutations in the sg promoter region confirmed a functional role for the RNA secondary structure, not the sequence. This study provides comprehensive bioinformatic resources for future functional studies of MNV and other caliciviruses.


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